Studies of Autism Spectrum Disorder (ASD) have reported progressively higher prevalence estimates, ranging from 0.07 to our recent report of 2.64%. While the evidence suggests that most of the rise is attributable to greater public awareness, a broadening of the ASD diagnostic criteria and better case ascertainment, it still remains possible that the rising ASD prevalence is associated with increases in ASD incidence. In turn, since purely genetic factors are unlikely to have an impact in such a short period of time increases in ASD incidence suggest that environmental factors and their interactions with genetic vulnerability are mechanisms for increasing risk for ASD. Detecting the etiological substrates of ASD has proven to be challenging. These difficulties likely arise from the complexity of ASD genetics, including gene-environmental interaction (GEX), insufficient sample sizes and the use of mainly clinical samples that may reflect biased selection. This proposal is designed to overcome these obstacles, and aims to discover etiologic substrates of ASD and determine their relationship to ASD incidence. This goal will be achieved by first prospectively examining cumulative incidence up to age 7 using 5 successive birth cohorts from Goyang City, South Korea, using a total population strategy and systematic, standardized case identification procedures. In this process, we will establish a systematically-ascertained population-based cohort of children with ASD, their families and sex and IQ matched controls from which we will collect data from medical histories, neuropsychological testing and physical examinations, along with blood for measurement of hormones and putative environmental toxins. With these data, we will examine the role of environmental risks in ASD incidence and phenotype. Finally, we will establish a biorepository of serum for further analyses, including toxins and ASD-related immunological markers, while also creating cell lines and purified DNA that can be used for future genetic and GEX studies. While these materials will be available for a subsequent large scale GEX study in which we will complete whole genome genotyping to provide sufficient coverage for environmentally responsive genes, in years 4 and 5 of the proposed study, we will also examine GEX using rapidly evolving data and replicated genetic markers from ongoing ASD genetic studies. When the proposed sample collection is completed, it will be analyzed independently and then combined with the data from our large-scale, Simons Foundation-funded epidemiological sample (N=10,000) whose saliva/blood were collected and phenotype was measured for ASD symptoms. This combination will dramatically increase the power and provide substantial opportunities to address ASD genetic architecture, the role of environmental factors and GEX in a large-scale, statistically well-powered, systematically-ascertained, population-based, genetically homogenous group of distinct individuals with ASD, along with matched controls. PUBLIC HEALTH RELEVANCE: Progressive increases in Autism Spectrum Disorder (ASD) prevalence, from 0.07 to 2.64%, represent a significant public health concern. It remains unclear whether changes in ASD incidence are contributing to such increased rates of ASD; this uncertainty may lend credence to concerns that environmental factors and gene-environmental interactions (GEX) are increasing the risks for ASD. Detecting the causes of ASD has proven to be challenging for many reasons, including the complexity of ASD genetics and GEX, as well as the difficulty in doing adequately designed studies. This proposal will use a very large, total population study of children with ASD, their families and matched controls, to identify some causes of ASD by first estimating ASD cumulative incidence and then examining the roles of environmental factors and GEX in creating risks for ASD.